The serine protease HtrA1 (PRSS11; Clan PA, family S1) belongs to an evolutionarily conserved family of HtrA proteins (Clausen, T., et al., Nat Rev Mol Cell Biol 12:152-62 (2011); Clausen, T., et al., Mol Cell 10:443-55 (2002)). In humans, HtrA1, 3, and 4 share the same domain architecture: an N-terminal IGFBP-like module and a Kazal-like module, a protease domain with trypsin-like fold, and a C-terminal PDZ domain. The physiological relevance of HtrA1 has been firmly established by the identification of human loss-of-function mutations causing familial ischemic cerebral small-vessel disease (Hara, K., et al., N Engl J Med 360:1729-39 (2009)). The molecular mechanism involves deficient TGF-β inhibition by HtrA1 resulting in increased TGF-β signaling (Hara et al., 2009). Dysregulated TGF-β signaling by aberrant HtrA1 expression may also contribute to arthritic disease (Oka, C., et al., Development 131:1041-53 (2004); Tsuchiya, A., et al., Bone 37:323-36 (2005)), perhaps in conjunction with HtrA1-mediated degradation of various extracellular matrix components (Chamberland et al., J Biol Chem 284:27352-9 (2009); Grau, S., et al., J Biol Chem 281:6124-9 (2006); Hadfield, K. D., et al., J Biol Chem 283:5928-38 (2008); Tocharus, J., et al., Dev Growth Differ 46:257-74 (2004); Tsuchiya et al., 2005)), or indirectly via up-regulation of matrix metalloproteases (Grau et al., 2006). In addition, human genetic studies identified a strong correlation between progression of age-related macular degeneration and a SNP in the HtrA1 promoter region, which results in increased HtrA1 transcript levels (Dewan, A., et al., Science 314:989-92 (2006); Yang, Z., et al., Science 314:992-3 (2006)). Therefore, inhibition of HtrA1 enzymatic function is an attractive therapeutic approach, e.g. in age-related macular degeneration and in arthritic disease.